CENTER FOR DRUG EVALUATION AND
`
`‘
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-3 04
`
`OTHER REVIEW! SQ
`
`

`

`u/5[oa
`
`
`
`Date:
`
`To:
`
`Through:
`
`M E M O R A N D U M
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`November 4, 2008
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia, Analgesia, and Rheumatology Products
`(DAARP)
`
`Michael Klein, Ph.D., Director
`Silvia Calderon. Ph.D., Team Leader
`Controlled Substance Staff (CSS)
`
`From:
`
`Lori A. Love, M.D. Ph. D ,Medical Officer
`Controlled Substance Staff
`
`Subject:
`
`-
`
`Tapentadol HCl (NDA 22-304), immediate release
`50 mg, 75 mg and 100 mg tablets
`Indication: Relief of moderate to severe acute pain
`Sponsor: Johnson & Johnson Pharmaceutical Research and
`Development, L.L.C. (J&JPRD)
`
`this memorandum provides expanded justification for CSS’
`the request of DAARP,
`At
`recommendation to consider the possibility of requiring additional postmarketing requirements in
`addition to Controlled Substance Act (CSA) scheduling. The basis for the recommendation is to
`ensure that the benefits of tapentadol outweigh the—risks and include the requirement of a
`Medication Guide. CSS recognizes that tapentadol is being introduced as an immediate release
`formulation and that there is no precedent for the requirement of a Medication Guide for
`immediate release opioids. However tapentadol exhibits the following distinctive properties
`indicating a high potential for abuse:
`
`1. Tapentadol is a new molecular entity analgesic that displays high affinity and selectivity for
`the u opioid receptor, and additionally inhibits the reuptake of norepinephrine.
`It is an
`atypical p. opioid agonist
`in that does not structurally resemble other opioids such as
`morphine.
`
`2.
`
`tapentadol
`In a human abuse liability phannacology study conducted by the Sponsor,
`displays high abuse potential comparable to that of hydromorphone, a drug thatis associated
`with high levels of abuse In this study single doses of tapentadol (50, 100, and 200 mg) had
`a similar abuse liability profile of subjective effects to that of calculated equianalgesic single
`doses of 4 mg, 8 mg, and 16 mg of hydromorphone, respectively.
`
`

`

`3. Based on the human abuse liability study and from the point of View of the potential for
`abuse, 50 mg of tapentadol (lowest tablet strength to be marketed) produces comparable
`opioid effects (liking, euphoria, etc) to that of 4 mg of hydromorphone.
`
`4. The CSA imposes tight controls in the manufacturing, importation/exportation, distribution
`and prescription of Schedule II opioids, leaving patients outside the regulatory loop created
`by the Act. Thus, to avoid high levels of misuse and abuse of tapentadol, which might
`counterbalance the beneficial therapeutic properties of the drug, it is recommended that
`physicians and patients receive training and education1n the use of the drug product from the
`time it is introduced on the market.
`
`5. CSS recognizes that there are few mechanisms to reach and educate health care professionals
`that will prescribe tapentadol tablets, as well as for patients and family members on the
`appropriate use of this novel analgesic. CSS suggests that a medication guide that emphasizes
`the following may be appropriate for tapentadol IR:
`
`0 Tapentadol is a u opioid agonist with effects and adverse events, including addiction
`and abuse, similar to other streng opioids, such as hydromorphone and oxycodone.
`This point needs to be emphasized in the product labeling.
`- Tapentadol ]R is only approved for acute usage, and should not be used chronically as
`this increases the adverse event profile, including the likelihood for addiction and
`abuse.
`_
`Specific instructions on appropriate patient selection and drug dosing should be
`provided such as [don’t take more than directed, what to do in case of a missed dose,
`don’t share drug, how to safely store the drug, etc,].
`
`0
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`Tapentadol HCI (NDA 22-304), immediate release
`
`2 of 2
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Lori Love
`11/4/2008 03:56:57 PM
`MEDICAL OFFICER
`
`Silvia Calderon
`11/4/2008 04:11:15 PM
`CHEMIST
`
`'
`
`Michael Klein
`11/5/2008 12:59:52 PM
`PHARMACOLOGIST
`
`

`

`
`
`M E M O R A N D U M
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`
`
`Date:
`
`To:
`
`October 17, 2008
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia, Analgesia, and Rheumatology Products
`
`Through:
`
`D
`
`Michael Klein, Ph.D., Director
`Controlled Substance Staff
`
`From:
`
`Subject:
`
`Lori A. Love, M.D., Ph.D., Medical Officer
`Controlled Substance Staff (CSS)
`
`Tapentadol HCl (NDA 22-304), immediate release
`50 mg, 75 mg and 100 mg tablets
`Indication: Relief of moderate to severe acute pain
`Sponsor: Johnson & Johnson Pharmaceutical Research and
`Development, L.L.C. (J&JPRD)
`
`Materials received: NDA 22-304 is located in the EDR.
`
`Submission:
`
`recommendations to the Division of Anesthesia, Analgesia, and
`This review provides
`Rheumatology Preducts (DAARP) regarding the abuse potential of tapentadol}.
`
`I. Background
`
`Tapentadol is a new molecular entity with CNS analgesic properties. It has both it opioid agonist
`receptor agonist properties and inhibits the reuptake of norepinephrine (NE). Both properties are
`relevant for the management of pain. Tapentadol 50 mg, 75 mg and 100 mg tablets is indicated
`for the relief of moderate to severe acute pain.
`
`In clinical studies tapentadol showed comparable potency to other Schedule II narcotics such as
`morphine and oxycodone, and showed a similar abuse potential profile of subjective effects to
`that of calculated equianalgesic doses of hydromorphone. The sponsor in their scheduling
`
`‘ Information for this review was also taken from: E. Fields, DFS Clinical Review NDA 22-304, 09/18/2008 and D. Lee, DFS Clinical
`Pharmacology Review NDA 22-304, 9/30/08.
`
`

`

`information requested that
`Substance Act (CSA).
`
`tapentadol be scheduled under Schedule II of the Controlled
`
`ll. Conclusions and Recommendations
`
`0 Receptor binding studies show that tapentadol displays high affinity and selectivity for u
`opioid receptors and inhibits the reuptake of NE. Drugs that bind to the u opioid
`receptors with high affinity have abuse potential and include such Schedule II drugs as
`morphine, oxycodone and hydromorphone.
`
`o Tapentadol, like morphine, has rewarding effects1n rats and acts as a positive reinforcer
`in monkeys.
`
`to induce physical dependence of the opioid type as
`o Tapentadol has the potential
`demonstrated in animal studies of withdrawal and in the clinical setting.
`
`0
`
`In a clinical abuse potential study conducted in subjects with a prior history of opioid
`abuse, single doses of 50 mg, 100 mg and 200 mg of tapentadol had a similar abuse
`potential profile of subjective effects to that of single doses of 4 mg, 8 mg and 16 mg of
`hydromorphone respectively Thus, a 50 mg dose of tapentadol, which represents the
`lowest available dosage strength, will produce similar euphorigenic and subjective effects
`to that of 4 mg of hydromorphone, a dose currently associated with high levels of abuse.
`
`0 CSS concurred with the Sponsor’s proposal for control of tapentadol1n Schedule II of the
`CSA and consequently initiated the procedure to finalize this action.
`
`0 Although tapentadol will be subject to Schedule 11 controls as is hydromorphone, the
`risks of abuse and misuse of tapentadol
`is high, and might
`require additional
`postrnarketing efforts that go beyond scheduling controls to maintain a positive benefit-
`risk assessment.
`
`Ill. Summary
`
`A. Clinical Studies
`
`immediate
`trials were completed during the development of tapentadol
`Thirty-one clinical
`release (IR) formulation (20 Phase 1, and 11 Phase 2/3 double-blind studies). The efficacy and
`safety of tapentadol in the treatment of moderate to severe acute pain was established in two
`randomized, double-blind, placebo- and active-controlled (Oxycodone) studies of moderate to
`severe pain from first metatarsal bunionectomy (Study KF5503/32) and end-stage degenerative
`joint disease (Study KF5503/33), using tapentadol in doses of 50 mg, 75 mg, and 100 mg every 4
`to 6 hours.
`.
`
`B.‘ Chemistry and Pharmacology
`Tapentadol HCl tablets are immediate—release film-coated tablets. The chemical name is 3-
`[(1R,2R)-3-(dimethylamino)—l—ethyl-2-methylpropyl]phenol monohydrochloride. The structural
`formula is:
`
`Mtapentadol IR NDA 22-304 CSS reviein-l7-08.doc
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`

`OH
`
`. HCl
`
`(R)
`
`(R)
`. N/
`un-
`
`The pKa values are 9.34 and 10.45.
`
`— Pharmacodynamics
`Tapentadol is 18-times less potent than morphine in binding to the human u opioid receptor and
`is 2-3 times less potent in producing analgesia in animal models, consistent with its dual mode of
`action. Unlike morphine, tapentadol also inhibits norepinephrine reuptake resulting in increased
`norepinephrine concentrations. Tapentadol exerts its pharmacodynamic effects directly without
`a pharrnacologically active metabolite.
`
`- Pharmacokinetics
`
`rapidly and completely absorbed after oral administration. Mean absolute
`is
`Tapentadol
`bioavailability after single-dose administration (fasting) is approximately 32% due to extensive
`first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at
`around 1.25 hours after dosing. The terminal half-life is on average 4 hours afier oral
`administration. The total clearance is 1530 +/- 177 ml/min.
`
`Dose-proportional increases in the Cmax and AUC values of tapentadol have been observed over
`the oral therapeutic dose range. A multiple (every 6 hour) dose study with doses ranging from 75
`to 175 mg tapentadol showed a mean accumulation factor of 1.6 for the parent drug and 1.8 for
`the major metaboliteitapentadol-O-glucuronide, which are primarily determined by the dosing
`interval and apparent half-life of tapentadol and its metabolites.
`
`- Metabolism and elimination
`
`About 97% of the parent compound is metabolized, primarily via conjugation with glucuronic
`acid to produce glucuronides. Following oral administration approximately 70% (55%
`glucuronide and 15%, sulfate of tapentadol of the dose is excreted in urine in the conjugated
`form, and 3% of drug was excreted unchanged. Tapentadol is additionally metabolized to N-
`desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 to hydroxytapentadol (2%) by CYP2D6,
`which are further metabolized by conjugation. None of the metabolites contributes to the
`analgesic activity. Tapentadol and its metabolites are excreted almost exclusively (99%) via the
`kidneys.
`
`C. Abuse Potential
`
`- Receptor Binding Studies
`Receptor binding studies show that tapentadol has higher affinity for u opioid receptors than for
`K and 8 receptors. Tapentadol binds to u opioid receptors labeled with naloxone with a Ki of 96
`nM, showing less affinity for 5 receptors labeled with the ligand DPDPE (Ki= 970 nM) and for K
`receptors labeled with the selective ligand CI-977 (Ki= 910 nM). In receptor binding studies on
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`cloned human u opioid receptors labeled with titrated naloxone, tapentadol showed high affinity
`with a Ki of 60 nM, whereas its major metabolite, the phenolic O-glucuronide derivative showed
`no relevant binding affinity at the human u opioid receptor up to- a concentration of 10 uM
`
`Tapentadol showed strong agonist activity comparable to that of morphine in stimulating u
`opioid'receptor-mediated G-protein activation using agonist-stimulated [3SS]GTPVS binding in
`cells expressing the cloned human p. receptors.
`
`In addition to its opioid activity, tapentadol inhibits the reuptake of NE with a Ki of 480 nM and
`has weak inhibitory activity on the 5-HT uptake of rat brain synaptosomes. The fr; Viva
`relevance of the effects of tapentadol on NE and 5-HT transporter systems was evaluated in a
`microdialysis study in rats. Tapentadol elicited a dose-dependent increase of extracellular levels
`of NE in the ventral hippocampus (up to approx. 450% above baseline) and, to a much lesser
`extent,_ of 5-HT (approx. 130% above baseline). Morphine did not increase NE concentrations
`but tended to increase 5-HT concentrations.
`
`- Subjective Effects, Drug Discriminatidn Studies
`Tapentadol in doses of 1-10 mg ip in rats showed a dose-dependent, firll generalization to the
`morphine (3.16 mg/kg) training cue, but did not produce an amphetamine—appropriate response.
`Morphine also showed a dose-dependent, fiill generalization to the morphine cue. The potency
`for generalization to a morphine cue was 2.4 times lower than the potency of morphine itself.
`These ratios are roughly equal to the potency differences in rat pain models and also to the
`relative potencies of these compounds in conditioned place preference studies.
`
`L Rewarding and Reinforcing Effects
`The rewarding effects of tapentadol were evaluated in the conditioned place preference paradigm
`in rats. Tapentadol and morphine produced a conditioned place preference at doses of 2.15
`mg/kg and 1.47 mg/kg, respectively. These results indicate that both morphine and tapentadol
`have rewarding effects. These positive preferences were antagonized by naloxone, indicating
`that the rewarding effects of these drugs mainly relate to their a opioid receptor activity. No
`locomotor sensitization was seen with any dose of tapentadol during the conditioning
`experiment.
`
`self-administration
`intravenous
`investigated in
`reinforcing properties were
`Tapentadol’s
`in Rhesus monkeys,
`trained to self-administer morphine
`sulfate
`(0.03
`experiments
`mg/kg/infiision). Tapentadol in the dose range of 0.01 to 0.3 mg/kg/infiision dose-dependently
`maintained self—administration behavior in morphine sulfate experienced monkeys.
`
`- Clinical Abuse Liability Studies
`The abuse potential of tapentadol (50 mg, 100 mg and 200 mg) was assessed relative to the
`Schedule II opioid, hydromorphone (4 mg, 8 mg and 16 mg) in 40 opioid-experienced, non-
`dependent subjects. The study design was an equianalgesic single-dose, double-blind, double-
`dummy, placebo-controlled,
`randomized,
`crossover
`(Study HP5503/14).
`The highest
`recommended therapeutic dose is 100 mg every 4 to 6 hours. Thus,
`the highest dose of
`tapentadol tested in the abuse liability study was twice the recommended therapeutic dose.
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`Several assessments and scales2 were used in the study to assess the positive and negative
`subjective drug effects produced by tapentadol and the Schedule 11 active comparator.
`Additional tests were used to evaluate the sedative, stimulant and the effects of tapentadol in
`comparison to hydromorphone and placebo-on cognitive performance.
`
`the primary
`The mean peak Overall Drug Liking scores over 24 hours postdose,
`pharmacodynamic endpoint of the study, for all the tapentadol doses were significantly different
`from placebo. Based on responses on a 100 mm VAS, the mean peak Overall Drug Liking
`scores increased in a dose-related manner afler administration of tapentadol (from 59.1 mm to
`73.0 mm) and the opioid hydromorphone (from 60.6 mm to 71.4 mm); after placebo, the mean
`peak score was 48.8 mm. Statistically significant differences were demonstrated between each
`tapentadol or hydromorphone dose and placebo and a similar dose-response relationship was
`observed between tapentadol and hydromorphone.
`
`The mean positive subjective effects for tapentadol and hydromorphone (Schedule II) tended to
`reach the highest values at one to two hours postdose. Both drugs decreased visual—motor
`coordination at the higher doses tested.
`
`- Dependence and Withdrawal
`The potential of tapentadol to produce physical dependence was examined in animal models and
`in the clinical trials setting.
`In‘ the acute mouse model, withdrawal was precipitated by a high
`dose of naloxone after two day pretreatment with increasing doses of tapentadol or morphine. In
`the chronic rat model, animals were pretreated for several weeks with either tapentadol or
`morphine, and withdrawal was induced by naloxone challenge (precipitated withdrawal) or by
`cessation of drug treatment (spontaneous withdrawal). In all animal experiments, the animals
`treated with tapentadol showed signs of physical withdrawal. However, tapentadol produced
`fewer Withdrawal symptoms than equianalgesic doses of morphine.
`
`Withdrawal was specifically evaluated in clinical study KF5503/34, a safety study where
`tapentadol was administered as flexible doses of 50 mg or 100 mg every 4 to 6 hours, as needed,
`over a 90 day period in subjects with low back pain or pain from knee or hip osteoarthritis.
`Assessment consisted of evaluation of treatment emergent adverse events of withdrawal during
`the trial, as a more formal assessment at the end of the study where tapentadol was withdrawn
`without taper. Subjects were evaluated using the Clinical Opiate Withdrawal Scale [COWS] and
`Subjective Opiate Withdrawal Scale [SOWSD at the follow-up visit.
`
`Subjects taking tapentadol appeared less likely to have withdrawal symptoms assessed with
`COWS than subjects with oxycodone (17% versus 29%). No difference in withdrawal symptom
`- severity was noted between the tapentadol and oxycodone groups, as assessed with SOWS total
`score.
`'
`-
`
`—h—
`
`2 Overall Drug Liking, Subject-Rated Opiate Agonist Scale, Addiction Center Inventory, Cole Version (Cole/ARCI), Subjective
`Effects Visual Analogue Scales (VAS), Subjective Drug Value, Observer-Rated Single-Dose Questionnaire, Divided Attention Test
`and Choice Reaction Time Test. The Cole ARCl includes Sedation, Unpleasantness-Dysphoria, Stimulation-Euphoria and Abuse
`Potential Subscales and the VAS include "Any Drug Effect”, “Good Drug Effects"," Bad Drug Effects", "High", "Take the Drug Again”
`and "Drug Liking" measures.
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`Nine subjects (1%) in the tapentadol group and 2 subjects (1%) in the oxycodone group reported
`drug withdrawal syndrome. Of these, a single case of withdrawal symptoms (elevated systolic
`blood pressure, irritability, and anxiety) was listed as a serious adverse event for a subject who
`had received treatment with tapentadol (250 mg to 600 mg total daily dose) for 94 days. Drug
`withdrawal syndrome was not reported in any other efficacy clinical trial.
`
`D. Clinical Safety
`- Adverse Events
`
`During clinical development, there were no deaths attributable to tapentadol IR. The adverse
`events reported were similar to those found with other related opioid; analgesics. The most
`common adverse reactions (reported by 210% in any tapentadol dose group) were nausea,
`dizziness, vomiting, somnolence, and headache. The incidence of vomiting, nausea and
`dizziness was noted to be lower for tapentadol
`than for hydromorphone. Euphoric mood,
`disorientation, confusional state, restlessness, hallucinations, agitation, nervousness, thinking
`abnormal, disturbance in attention, paraesthesia, sedation, depressed level of consciousness,
`memory impairment, ataxia and coordination abnormal, dyspnea, respiratory depression and
`decreased blood pressure were reported in less than one percent of tapentadol treated subjects.
`
`- Overdose
`
`No case of overdose was reported in the completed studies with tapentadol IR. One subject who
`received tapentadol ER in an ongoing 1-year, open-label, Phase 3 clinical study (KF5503/24)
`reported an overdosage with euphoria and visual disturbance.
`
`- Drug Accountability and Diversion
`
`Drug accountability and compliance with study drug treatment was assessed for the 3 longer—
`terrn Phase 3 clinical studies (KF5503/33 [10 days], KF5503/34 [90 days], and the open-label
`extension period in KF5503/32 [9 days]. A small number of patients self-administered more ,
`than the intended daily dose of tapentadol IR, up to 1200mg/day for one or two days. All
`subjects had prior opioid experience and none reported an adverse event.
`In study KF5503/34,
`fewer subjects in the tapentadol IR group (9%) than in the oxycodone IR group (12%) took more
`than 14 capsules onany day for 1 or more days.
`'
`
`There were no reports of study drug diversion.
`
`- Postmarketing Risk Management
`The sponsor identified important and potential risks associated with tapentadol IR in Table 1,
`and proposed routine and product specific pharmacovigilance to address these concerns.
`
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`Table 1: Summary ofS_afety Concerns
`
`Safety Concerns
`Important identified risks:
`Potential for abuse
`Seizure
`Important potential risks:
`Overdose
`Oil-label use. incl. pediatric patients
`Potential for medication errors (inappropriate
`prescribing. inappropriate dosing. inappropriate
`use) and patient misuse
`Accidental exposure
`
`Diversion
`Important missing information:
`Use in pediatrics
`Source: Tapcntadol [R Safety Surveillance Plan
`
`From the data obtained during clinical development, the risks for abuse, misuse and diversion of
`tapentadol IR are likely to be extremely high, and safe use of this product will be contingent on
`effective management of these risks postmarketing. Although the agency has not as yet required
`a Risk Evaluation and Mitigation Strategy (REMS) for immediate release opioid products,
`consideration of a REMS may be appropriate for this product.
`
`APPEARS THlS WAY
`0N ORlGlNAL
`
`Mtapentadol IR NDA 22-304 CSS reviewlO—l7-08.doc
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`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/8/
`
`Lori Love
`10/17/2008 04:09:02 PM
`MEDICAL OFFICER
`
`Michael Klein
`10/17/2008 05:07:09 PM
`PHARMACOLOGIST
`
`